Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology

Abstract

Deafness-Dystonia-Optic Neuropathy (DDON) Syndrome is a rare X-linked progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene encoding for the deafness dystonia protein 1 (DDP1). Despite important progress in identifying and characterizing novel mutations in this gene, little is known about the underlying pathomechanisms. Deficiencies in the biogenesis of hTim23 and consecutive alterations in biogenesis of inner membrane and matrix proteins have been proposed to serve as one possible mechanistic explanation. To shed new light on the role of DDP1 in the biogenesis of mammalian mitochondria, we investigated the effects of reduced or elevated DDP1 levels on mitochondrial dynamics and function. Our results show a reduction in the import of β-barrel proteins into mitochondria from cells overexpressing DDP1. This effect was not observed when the DDON-related mutant form DDP1-C66W was overexpressed. Live cell microscopy of primary fibroblasts derived from DDON patients and of DDP1 downregulated HeLa cells displayed alterations of mitochondrial morphology with notable extensions in the length of mitochondrial tubules, whereas overexpression of DDP1 induced the formation of hollow spherical mitochondria. Of note, knockdown of the TIMM8A gene by RNA interference did not show an influence on the oxygen respiration rate and the mitochondrial membrane potential. Taken together, these results suggest that alterations in the levels of DDP1 can affect the morphology of mitochondria and thus shed new light on the pathogenic mechanisms of DDON.

A homozygousFITM2mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

“…Mohr–Tranebjaerg syndrome with defects in TIMM8A . TIMM8A is located in the mitochondrial intermembrane space and functions in mitochondrial morphology ( Engl et al ., 2012 ). Alternative and/or additional pathogenic mechanisms for the presented syndrome might be related to ER-stress, analogous to the disease mechanism of motor neuropathies that arise from gain-of-function mutations in BSCL2 , which encodes seipin, a protein that functions in LD biogenesis ( Ito and Suzuki, 2009 ; Cartwright et al ., 2015 ).…”

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…A recent study tested the effects of elevated or reduced DDP1 levels on mitochondrial morphology, energy production, cellular viability and protein import [73]. Bioenergetic properties were unchanged in patient fibroblasts and DDP1 knock-down cells compared to controls, but the import of beta-barrel proteins and mitochondrial morphology was abnormal.…”

Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations

“…The voltage-dependent anion selective channel protein 1 (VDAC1) (21, 22) and prohibitin (23) are integral proteins, anchored to the outer and inner membranes, respectively. The mammalian mt ribosome (3), cytochrome c (Cyt c) (24), creatine kinase (CKMT1A) (25), and heat shock protein 60 (Hsp60) (26, 27) are reported to be dual localized in the soluble and membranes fractions as peripheral proteins. All marker proteins were detected in agreement with the literature (Fig.…”